Project Summary Evidence exists that the risk for a wide range of chronic diseases increases with age. For many of these diseases effective pharmacological interventions are lacking. Hence, any intervention that can slow aging can also reduce the potential of contracting such illnesses. Although several compounds are currently under investigation for their life span extending effects, the complexity of the aging phenotype makes this search difficult. In this project we combine two emerging strategies for drug discovery, namely in silico pharmacology and the use of invertebrate whole-animal models. Aim 1 will provide a collection of candidate compounds by performing a large-scale bioinformatics screen of over 1,300 pharmacological agents. To do this we will utilize a novel gene list comparison algorithm we have developed to identify significant associations between expression changes induced by drug treatment and expression changes observed in interventions that extend healthspan. Aim 2 will test the effect of drugs identified in Aim 1 in Drosophila melanogaster. Flies will be fed each compound over the course of their adult life, and their life span as well as their response to stressors will be monitored and compared to that of flies on control food. The proposed work will develop an important new bioinformatics strategy to screen for longevity drugs and has the potential to identify several novel compounds that extend life span. Aim 3 will utilize the same data collected in Aim 1 but will use a complementary approach in which shared regulatory elements will be identified in the promoters of the genes in the common signatures between drugs and healthspan interventions.